1. Field of the Invention
The invention relates to the preparation of aminomethylene compounds by aminomethylenation of C--H acid compounds in a one-step reaction. Aminomethylene compounds, such as aminomethylenated dinitriles, cyanoacetic esters and malonic esters, are important C.sub.3 or C.sub.4 building blocks in the synthesis of heterocycles, such as, for example, pyrazole, pyridine and quinoline derivatives, which find application as pharmaceutical active compounds and plant protection agents (U.S. Pat. No. 4,620,865).
2. Description of the Related Art
It is known that C--H acid compounds can be aminomethylenated by reaction with dimethylformamide (DMF) and auxiliaries. If, for example, a ten-fold molar excess of acetic anhydride is used as the auxiliary, yields of 20 to 40% of the theoretical yield of aminomethylenated substances are obtained after heating for 5 to 7 hours under reflux (Arch. Pharm. 295 (1962), 516). With variation of the reaction conditions to improve the space-time yield, larger amounts of carbon monoxide are formed according to DD 151,624. If the acetic anhydride is replaced by POCl.sub.3 and the reaction is carried out in excess DMF, about 47% of reaction product is obtained when using methyl cyanoacetate as the C-H acid compound (Z. obs. chim. 32 (1962), 4050, cited in DD 151,624). The conduct of the reaction and the working up are very complicated. If the variant mentioned is carried out using POCl.sub.3 in benzene, only 7% of reaction product is isolated (Chem. Ber. 94 (1961), 2278). If ethyl chloroformate is used as the auxiliary, only 31% of the theoretical yield is obtained in the case of cyanoacetic ester on account of side reactions occurring. The use of phosgene gives 81% of the theoretical yield in the case of diethyl malonate using an excess of sodiomalonic ester as base. With ethyl cyanoacetate, 75% of the theoretical yield is obtained using triethylamine as base (Chem. Ber. 94 (1961), 2278). However, the use of sodiomalonic ester is expensive, on the other hand with triethylamine complicatedly large amounts of triethylamine hydrochloride have to be separated off.
According to DD 257,067, the reaction of cyanoacetate with the DMF-dimethylsulfate-adduct and sodium carbonate as the base leads to 53-61 % of the theoretical yield of the aminomethylenated product, however the non-uniform fusion point points to impurities.
Without base, the aminomethylenation can be carried out using thionyl chloride. In this case, the reaction mixture has to heated under reflux conditions in tetrachloromethane for 5 hours in order to obtain a yield of 79% of ethyl dimethylamino-cyanoacetate. However, the black crude product has to be recrystallized so that in the most favorable case (with a 25% excess of DMF and thionyl chloride) 68% of the theoretical yield of clean substance can be isolated (DD 151,624). Some tests showed that when using the less problematical solvent toluene 15% less reaction product is again obtained. An aminomethylenation of malonic ester is not possible by this method.
Additionally, in reactions with DMF and chlorinating agents, such as PCl.sub.5, POCl.sub.3, SOCl.sub.2, COCl.sub.2 and the like, the carcinogenic N,N-dimethylcarbamoyl chloride is formed as a secondary component, so that the handling and use of the product thus prepared is problematical; use is only possible after complicated purification steps.
Aminomethylenation using the combination Gold's salt/sodium methoxide leads after heating to reflux in ethanol overnight to a yield of 55 to 82% of the theoretical yield (Synth. Commun. 12 (1982), 939). Working up is complicated, and the reaction product still has to be additionally recrystallized. A large excess of DMF is required in order to prepare the Gold's salt. This and also the isolation of the salt is relatively cost-intensive, so that industrial production is too expensive.
Aminomethylenation with amidines or with the combination orthoester/sec.-amine is uneconomical because of the expensive reagents. Condensation with amide acetals and aminal esters is also unfavorable in terms of cost because of the troublesome manner of preparation of these orthoamides. DMF acetals are thus prepared by alkylation with alkyl sulphates (Chem. Ber. 96 (1963), 1350) and subsequent reaction with alkali metal alkoxides (Chem. Ber. 101 (1968), 41). The isolation from the alcoholic reaction mixture according to DD 94,359 is troublesome and time-consuming. A supposedly improved distillation process mentioned in this East German Patent is referred to in DD 151,624 already mentioned above as difficult to realize industrially. Additionally, it was not possible to achieve the high yield indicated in a reworking in a laboratory manner.
The aminal esters are accessible by reaction of the DMF-dialkyl sulphate adducts with dimethylamine and then with alkali metal alkoxides in hexane, cyclohexane or ether (Chem. Ber. 101 (1968), 41). The yields are 77 to 84% in condensations of C--H acid compounds with dimethylformamide-diethyl acetal, at most 89% with the methyl aminal ester; the acetal is accessible in 63% of the theoretical yield from the DMF-dimethyl sulphate adduct, while the methyl aminal ester is obtainable in 62% of the theoretical yield, starting from tetramethylformamidinium methylsulphate.